It is now recognized that the gut microbiota ? the collection of microbes endemic to the normal human digestive tract ? plays a major role in regulating health, and adjusting the balance of the microbiota has been proposed as a therapeutic strategy. However, no work has yet explored the possibility of engineering these endemic bacteria as safe and tunable vehicles for delivery of therapeutic functions to treat genetic disorders. I propose to test the feasibility of this approach by establishing a therapeutic strategy for a group of potentially lethal autosomal recessive disorders collectively called inborn errors in metabolism (IEMs), a group that includes diseases like Phenylketonuria (PKU), Tyrosinemia, and Maple Urine Disease (MSUD). Individually, most of these disorders affect just 1 or fewer in 10,000 newborns, but collectively, IEMs have an incidence rate of approximately 1 in 1,000. The pathologies of these disorders stem from improper metabolism of components present in food, particularly in breast milk, resulting in synthesis of toxic byproducts that can lead to severe developmental disorders in newborns. Death can result in cases where the disorder is not diagnosed early enough to implement appropriate interventions. Few attempts have been made to find treatments for these diseases and currently, the only intervention for most is a severely restricted diet, and that is often only partially effective. My lab is interested in using the tools of synthetic biology to develop a novel microbe-based therapeutic platform for treating IEMs. The amino acids that cause pathologies in IEMs are absorbed in the small intestine and then metabolized to produce toxic products. To minimize the toxicities, we propose to take advantage of microbes that naturally colonize the human small intestine and engineer them to produce enzymes that specifically intercept and metabolize the offending amino acids prior to absorption, generating non-toxic metabolites. We will develop a platform for this metabolic redirection using engineered enzymes expressed in bacteria that have also been engineered to maintain sufficient residence times in the gut to allow long-term therapeutic benefit. These bacteria will also be re-programmed for tunable metabolic re-direction and for population control that can be regulated using ingestible chemical signals. Such a strategy could provide much needed therapeutics for treating IEMs, and has strong potential as an approach to treating other types of metabolic disorders and gut infections as well.